Population-based tobacco treatment: study design of a randomized controlled trial.
Most smokers do not receive comprehensive, evidence-based treatment for tobacco use that includes intensive behavioral counseling along with pharmacotherapy. Further, the use of proven, tobacco treatments is lower among minorities than among Whites. The primary objectives of this study are to: (1) Assess the effect of a proactive care intervention (PRO) on population-level smoking abstinence rates (i.e., abstinence among all smokers including those who use and do not utilize treatment) and on utilization of tobacco treatment compared to reactive/usual care (UC) among a diverse population of smokers, (2) Compare the effect of PRO on population-level smoking abstinence rates and utilization of tobacco treatments between African American and White smokers, and (3) Determine the cost-effectiveness of the proactive care intervention. This prospective randomized controlled trial identifies a population-based sample of current smokers from the Department of Veterans Affairs (VA) electronic medical record health factor dataset. The proactive care intervention combines: (1) proactive outreach and (2) offer of choice of smoking cessation services (telephone or face-to-face). Proactive outreach includes mailed invitation materials followed by an outreach call that encourages smokers to seek treatment with choice of services. Proactive care participants who choose telephone care receive VA telephone counseling and access to pharmacotherapy. Proactive care participants who choose face-to-face care are referred to their VA facility's smoking cessation clinic. Usual care participants have access to standard smoking cessation services from their VA facility (e.g., pharmacotherapy, smoking cessation clinic) and from their state telephone quitline. Baseline data is collected from VA administrative databases and participant surveys. Outcomes from both groups are collected 12 months post-randomization from participant surveys and from VA administrative databases. The primary outcome is self-reported smoking abstinence, which is assessed at the population-level (i.e., among those who utilize and those who do not utilize tobacco treatment). Primary analyses will follow intention-to-treat methodology. This randomized trial is testing proactive outreach strategies offering choice of smoking cessation services, an innovation that if proven effective and cost-effective, will transform the way tobacco treatment is delivered. National dissemination of proactive treatment strategies could dramatically reduce tobacco-related morbidity, mortality, and health care costs. ClinicalTrials.gov: NCT00608426.


Protective roles of home and school environments for the health of young Canadians.
The relationships of home and school environments, health risk behaviours and two sentinel adolescent health outcomes were examined in an aetiological analysis. The analysis focused on determinants of the health of young people and the role of school settings in the optimisation of health. Records were examined from the Canadian sample of the Health Behaviour in School-aged Children (HBSC) Survey. 3402 young people in Ontario, Canada were administered this survey in 2006, of which 1966 were re-administered the survey 1 year later and supplied complete data. Individual items and factor-analytically derived scales were used to examine potential aetiological relationships in a series of structural equation models. Health outcomes examined were serious injury and psychosomatic symptoms. Models developed from cross-sectional data were confirmed longitudinally. Adolescents who reported negative home and school environments reported higher levels of substance use, psychosomatic symptoms and serious injuries (the latter identified in longitudinal analysis only). Engagement in health risk behaviour partially mediated the link between these two environments and the sentinel health outcomes. Positive school environments were protective in that they moderated associations between negative home environments and engagement in health risk behaviours. The effects observed in longitudinal analyses were generally consistent with those observed cross-sectionally. Negative home environments clearly place adolescents at risk for engagement in health risk behaviours and associated physical health outcomes. Positive school environments can in part moderate these relationships. Optimisation of school social environments therefore remains warranted as a population health strategy.


The leukemia-associated Mllt10/Af10-Dot1l are Tcf4/β-catenin coactivators essential for intestinal homeostasis.
Wnt signaling maintains the undifferentiated state of intestinal crypt progenitor cells by inducing the formation of nuclear TCF4/β-catenin complexes. In colorectal cancer, activating mutations in Wnt pathway components cause inappropriate activation of TCF4/β-catenin-driven transcription. Despite the passage of a decade after the discovery of TCF4 and β-catenin as the molecular effectors of the Wnt signal, few transcriptional activators essential and unique to the regulation of this transcription program have been found. Using proteomics, we identified the leukemia-associated Mllt10/Af10 and the methyltransferase Dot1l as Tcf4/β-catenin interactors in mouse small intestinal crypts. Mllt10/Af10-Dot1l, essential for transcription elongation, are recruited to Wnt target genes in a β-catenin-dependent manner, resulting in H3K79 methylation over their coding regions in vivo in proliferative crypts of mouse small intestine in colorectal cancer and Wnt-inducible HEK293T cells. Depletion of MLLT10/AF10 in colorectal cancer and Wnt-inducible HEK293T cells followed by expression array analysis identifies MLLT10/AF10 and DOT1L as essential activators to a large extent dedicated to Wnt target gene regulation. In contrast, previously published β-catenin coactivators p300 and BRG1 displayed a more pleiotropic target gene expression profile controlling Wnt and other pathways. tcf4, mllt10/af10, and dot1l are co-expressed in Wnt-driven tissues in zebrafish and essential for Wnt-reporter activity. Intestinal differentiation defects in apc-mutant zebrafish can be rescued by depletion of Mllt10 and Dot1l, establishing these genes as activators downstream of Apc in Wnt target gene activation in vivo. Morpholino-depletion of mllt10/af10-dot1l in zebrafish results in defects in intestinal homeostasis and a significant reduction in the in vivo expression of direct Wnt target genes and in the number of proliferative intestinal epithelial cells. We conclude that Mllt10/Af10-Dot1l are essential, largely dedicated activators of Wnt-dependent transcription, critical for maintenance of intestinal proliferation and homeostasis. The methyltransferase DOT1L may present an attractive candidate for drug targeting in colorectal cancer.


Innovative green supercritical fluid chromatography development for the determination of polar compounds.
In the context of green analytical chemistry, a supercritical fluid chromatography method was developed. In order to prove the potential of this technology, a worst case was selected, i.e. the separation of very polar compounds. For that purpose, an innovative methodology based on design of experiments (DoE) and design space (DS) was previously developed and successfully tested on liquid chromatography. For the first time, this methodology was applied to a supercritical fluid chromatography (SFC) separation. First, a screening design was used to select the stationary phase and the nature of the mobile phase based on a maximization of the number of peaks eluted and a minimization of the number of co-eluted peaks. Then, a central composite design with orthogonal blocks defined a set of experiments used to model the retention times of each peak at the beginning, the apex, and the end. The gradient slope, the isocratic plateau before the gradient, the temperature, and the concentration of trifluoroacetic acid (TFA) in the mobile phase were the potentially influential factors. The critical quality attributes (CQAs), i.e. the separation (S) between peaks of the most critical pair, and the analysis time were the criteria considered to assess the quality of the separation. The DS was computed as the multidimensional subspace where the probability for the separation and analysis time criteria to be within acceptance limits was higher than a defined quality level. The DS was computed propagating the prediction error from the modeled responses to the quality criterion using Monte Carlo simulations. The optimal condition was predicted at a gradient slope of 3.8% min(-1) to linearly modify the modifier proportion between 5 and 40%, an isocratic time of 3min, a concentration of TFA of 25mM, and a temperature of 60.5°C. This optimal condition was experimentally tested to confirm the prediction. Furthermore, chromatographic conditions included in the DS and on the limits of the DS were experimentally tested to assess the robustness of the developed SFC method.


Forced diuresis and dual-phase F-fluorodeoxyglucose-PET/CT scan for restaging of urinary bladder cancers.
The results of (18)F-fluorodeoxyglucose (FDG)-PET imaging carried out with the current standard techniques for assessment of urinary tract cancers have been reported to be less than satisfactory because of the urinary excretion of the tracer. To investigate the role of dual-phase FDG-PET/CT in the restaging of invasive cancers of the urinary bladder, with delayed imaging after forced diuresis and oral hydration as the scanning protocol. FDG-PET has been considered to be of limited value for the detection of urinary tract cancers because of interference by the FDG excreted in urine. We investigated the efficacy of delayed FDG-PET/CT in the restaging of invasive bladder cancer, with imaging performed after intravenous (IV) administration of a potent diuretic and oral hydration. Twenty-nine patients with invasive cancer of the urinary bladder were included in this study. Patients were divided into two groups: Group I (22 patients) included cases with invasive bladder cancer who had not undergone cystectomy and group II (seven patients) included cases with invasive bladder cancer who had undergone cystectomy and urinary diversion procedure. All patients underwent FDG-PET/CT scan from the skull base to the mid-thighs 60 min after IV injection of 370 mega-Becquerel (MBq) of FDG. Additional delayed images were acquired 60-90 min after IV furosemide and oral hydration. PET/CT data were analyzed as PET and CT images studied separately as well as fused PET/CT images and the findings were recorded. The imaging findings were confirmed by cystoscopy, biopsy or follow-up PET/CT. The technique was successful in achieving adequate washout of urinary FDG and overcame the problems posed by the excess FDG in the urinary tract. Hypermetabolic lesions could be easily detected by PET and precisely localized to the bladder wall, perivesical region and pelvic lymph nodes. PET/CT delayed images were able to demonstrate 16 intravesical lesions (in 13 patients), with excellent clarity. Lymph node metastases were detected in a total of six patients. Of these, in two patients, FDG-avid lymph nodes were evident only in the delayed images. The information provided by the postdiuretic delayed images changed the PET/CT interpretation in 14 patients of invasive bladder cancer: Recurrent bladder lesions were identified in 12 patients, pelvic lymph node metastasis (only) in one patient and bladder lesion as well as lymph node metastasis in one patient. Distant metastases were detected by PET/CT in two cases. CT scan was false-negative for early recurrence in the bladder wall for seven of 16 lesions. CT also showed two false-positive lesions. There were no false-positives with PET. Detection of recurrent disease in cases of invasive bladder cancer can be significantly improved by using FDG-PET/CT, with delayed imaging following forced diuresis and oral hydration. Composite PET/CT is superior to CT alone for the restaging of invasive bladder cancers.


Von Gierke's disease adopts an orphan (and its partner).
The enzyme glucose-6-phosphatase is critical for maintaining fasting blood sugar levels by increasing hepatic glucose production. Its absence in patients with von Gierke's disease leads to severe hypoglycemia and abnormal accumulation of glycogen (glycogenosis) in the liver. New players that control the expression of glucose-6-phosphatase have been identified that may provide insight into this metabolic disorder, as well as type 2 diabetes.


Epidemiologic application of a standardized ribotype scheme for Vibrio cholerae O1.
A standardized scheme of 27 different BglI ribotypes and subtypes of Vibrio cholerae O1 strains is proposed on the basis of data from 214 human and environmental strains isolated in 35 countries and 14 U.S. states over the past 60 years. The ribotype patterns obtained are reproducible and stable over time. Seven different but very similar ribotypes (1a to 1g) were observed among 16 strains of the classical biotype. Twenty ribotypes and subtypes were identified among 198 V. cholerae O1 strains of the El Tor biotype. Six different patterns were found among the strains causing the current seventh pandemic. Strains of ribotype 8 originated only in central African countries, while those of ribotype 3 originated mainly in Asia and the Pacific Islands. The most widely distributed strains were those of ribotype 6, which was subdivided into three very similar but still distinguishable subtypes. The present Latin American epidemic is caused by strains of ribotype 5. Strains of this ribotype were isolated from several other geographic locations but can be differentiated from the Latin American strains by other molecular methods. Strains associated with two documented environmental reservoirs exhibited three distinct ribotype patterns; those isolated from patients who ate food from the U.S. Gulf waters were all of ribotype 2, while the strains related to the northeast Australian rivers were of ribotypes 9 and 10. Nontoxigenic V. cholerae O1 strains originating in Latin America and the U.S. Gulf Coast did not form a specific cluster of ribotypes. Ribotyping in combination with other well-defined methods can assist in epidemiologic investigations, helping to trace the movement of strains and to identify their geographic origins.


Systematic evaluation of dose proportionality studies in clinical pharmacokinetics.
An understanding of dose proportionality is essential in drug development, and the results are of great clinical importance for predicting the effects of dose adjustments. However, little consensus exists with regard to study design and analysis. The aim of this paper was to produce a detailed profile of the information on dose proportionality studies in the last 10 years and to provide a foundation for reflection and debate on future priorities. A total of 147 publications comprising 156 studies were analyzed. The typical dose proportionality study enrolled 20 to 30 subjects and randomly allocated them into 3 to 4 dose levels to investigate pharmacokinetic behaviors within a dose ratio range of 2-6. The most common design was the crossover experiment (52.6%), and evaluating dose-adjusted pharmacokinetic parameters followed by hypothesis testing (43%) was the most frequent statistical approach. However, the alternative crossover design and equivalence criterion based on the power model represented only 4% and 8% of studies, respectively. The power model as a recommendable empirical relationship to assess dose proportionality was applied in 25 (16%) studies. This research suggests that the alternative crossover design and power model statistical method should be attracting more attention in order to obtain more information in studies with limited subjects.


Coexistence in a metapopulation model with explicit local dynamics.
Many patch-based metapopulation models assume that the local population within each patch is at its equilibrium and independent of changes in patch occupancy. We studied a metapopulation model that explicitly incorporates the local population dynamics of two competing species. The singular perturbation method is used to separate the fast dynamics of the local competition and the slow process of patch colonization and extinction. Our results show that the coupled system leads to more complex outcomes than simple patch models which do not include explicit local dynamics. We also discuss implications of the model for ecological systems in fragmented landscapes.


Objective assessment of changes in nuclear morphology and cell distribution following induction of apoptosis.
To objectively measure changes in nuclear morphology and cell distribution following induction of apoptosis. A spontaneously immortalized retinal pigment epithelial cell line (ARPE-19) was cultured for three days in DMEM/F12 with 10% fetal bovine serum followed by 24 hours incubation in staurosporine to induce apoptosis. Cells that were not incubated in staurosporine served as control. Caspase-3 expression in apoptotic cells was demonstrated by quantitative immunofluorescence. Nuclei were counterstained with DAPI. Assessments of nuclear morphology and cell distribution were performed using ImageJ software. Statistical analyses included Student's t-test and Pearson's correlation coefficient. Nearest neighbor analysis was used to assess cell nuclei distribution. Caspase-3 expression in staurosporine-incubated cells increased by 471% ± 182% compared to control (P=0.014). Relative to the control, cells in the staurosporine-incubated cultures had smaller average nuclear area (68% ± 5%; P<0.001) and nuclear circumference (78 ± 3%; P<0.001), while nuclear form factor was larger (110% ± 1%; P<0.001). Cell nuclei from the staurosporine-group (R=1.12 ± 0.04; P<0.01) and the control (R=1.28 ± 0.03; P<0.01) were evenly spaced throughout the cultures, thereby demonstrating a non-clustered and non-random cell distribution. However, the staurosporine-incubated group had a significantly lower R-value compared to the control (P=0.002), which indicated a move towards cell clustering following induction of apoptosis. Caspase-3 expression of each individual cell correlated significantly with the following morphological indicators: circumference of the nucleus divided by form factor (r=-0.475; P<0.001), nuclear area divided by form factor (r=-0.470; P<0.001), nuclear circumference (r=-0.469; P<0.001), nuclear area (r=-0.445; P<0.001), nuclear form factor (r=0.410; P<0.001) and the nuclear area multiplied by form factor) (r=-0.377; P<0.001). Caspase-3 positive apoptotic cells demonstrate morphological features that can be objectively quantified using freely available ImageJ software. A novel morphological indicator, defined as the nuclear circumference divided by form factor, demonstrated the strongest correlation with caspase-3 expression. The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/3271993311662947.


The current situation in mexican immigration.
By 1988, the Mexican-origin population of the United States had grown to 12.1 million, largely from recent, sharp increases in immigration. The policy concerns raised by this phenomenon have been influenced by some perceptions that available research contradicts. Today most Mexican immigrants come to stay, about half are female, and they have increasingly less schooling compared to the native-born population and other immigrants. Nationally, they do not cause adverse economic effects for native-born workers and, across generations, their language and political assimilation is proceeding well. They put greater demands on education than on other public services. However, the Mexican-origin population affects the economy and public services more and differently in the areas where it is concentrated, primarily in the western United States and large urban areas. Further, the recent legalization of 2.3 million Mexican immigrants can be expected to increase the demand on public services, especially in those areas.


Dietary energy density but not glycemic load is associated with gestational weight gain.
Most pregnant women gain more weight than the ranges recommended. Excessive weight gain is linked to pregnancy complications and to long-term maternal and child health outcomes. The objective was to examine the impact of dietary glycemic load and energy density on total gestational weight gain and the weight gain ratio (observed weight gain/expected weight gain). Data are from 1231 women with singleton pregnancies who participated in the Pregnancy, Infection, and Nutrition Cohort Study. Dietary information was collected at 26-29 wk of gestation with the use of a semiquantified food-frequency questionnaire. Linear regression models were used to estimate the associations between quartiles of glycemic load and energy density with total gestational weight gain and weight gain ratio. Dietary patterns of pregnant women significantly differed across many sociodemographic and behavioral characteristics, with the greatest contrasts seen for glycemic load. After adjustment for covariates, compared with women in the first quartile consuming a mean dietary energy density of 0.71 kcal/g (reference), women in the third quartile consuming a mean energy density of 0.98 kcal/g gained an excess of 1.13 kg (95% CI: 0.24, 2.01), and women in the fourth quartile consuming a mean energy density of 1.21 kcal/g gained an excess of 1.08 kg (95% CI: 0.20, 1.97) and had an increase of 0.13 (95% CI: 0.006, 0.24) units in the weight gain ratio. All other comparisons of energy intakes were not statistically significant. Glycemic load was not associated with total gestational weight gain or weight gain ratio. Dietary energy density is a modifiable factor that may assist pregnant women in managing gestational weight gains.


Crystalluria and Chronic Kidney Disease.
Crystalluria can involve the kidney and lower urinary tract, can produce acute and chronic effects, and occurs in all mammalian species. Most commonly urinary crystals contain calcium. Numerous other endogenous and exogenous substances can produce crystalluria. Crystals are identified in kidneys of many species, up to 100% in certain rat strains. More severe renal disease (acute tubular necrosis and chronic renal disease) can be secondary to crystal accumulation, such as observed with melamine-cyanuric acid in cats and dogs. Aggregation of crystals leads to calculi that act as urothelial abrasives with consequent regenerative proliferation. Accumulation in the kidney pelvis or bladder can lead to partial or complete obstruction and hydronephrosis. Long-term presence of urinary tract calculi in rodents leads to increased risk of urothelial tumors, but not in humans. Crystals in the lower urinary tract can act as irritants in rodents, but not in humans. It is critical that specific procedures are followed to optimize the presence of crystals in urine for diagnosis, including not fasting the animals. Numerous factors have been identified which can enhance or inhibit crystal formation. Extrapolation from animals for the threshold toxicity of crystals/calculi is appropriate but is not relevant for cancer risk assessment.


Fundholding in northern region: the first year.
To describe the experiences of 10 fundholding practices in the Northern region during 1991-2 and to elicit subjective assessments of the impact of their change in status on practice management and patient care. Semistructured interviews were conducted with clinicians and practice managers; other staff in the practices were asked to fill in questionnaires. Questions were asked about the preparatory year, the impact of fundholding on clinical practice and practice management, perceptions of the costs and benefits of fundholding, and views about the future of the scheme. 10 of the 28 first wave fundholding practices in the Northern region, March-July 1992. Two interviews were conducted in nine practices and one interview in the tenth practice. Replies to the questionnaire were received from 35 general practitioners (73%) and 89 (58%) nonmedical staff. Practices sought independence in applying for fundholding status and found the preparatory year challenging and time consuming. General practitioners thought that the greatest change had occurred in relationships with consultants and the least change in relationships with patients. Most respondents thought that fundholding had changed the way they worked. The perceived benefits of fundholding were mentioned more often than the perceived costs. The results offer some encouragement to the proponents of fundholding, but more longitudinal studies are needed to evaluate the misgivings of critics of the scheme. Fundholders are uncertain about their ability to make savings year after year, particularly in an increasingly cost contained environment.


Optimizing the regularization for image reconstruction of cerebral diffuse optical tomography.
Functional near-infrared spectroscopy (fNIRS) is an optical method for noninvasively determining brain activation by estimating changes in the absorption of near-infrared light. Diffuse optical tomography (DOT) extends fNIRS by applying overlapping "high density" measurements, and thus providing a three-dimensional imaging with an improved spatial resolution. Reconstructing brain activation images with DOT requires solving an underdetermined inverse problem with far more unknowns in the volume than in the surface measurements. All methods of solving this type of inverse problem rely on regularization and the choice of corresponding regularization or convergence criteria. While several regularization methods are available, it is unclear how well suited they are for cerebral functional DOT in a semi-infinite geometry. Furthermore, the regularization parameter is often chosen without an independent evaluation, and it may be tempting to choose the solution that matches a hypothesis and rejects the other. In this simulation study, we start out by demonstrating how the quality of cerebral DOT reconstructions is altered with the choice of the regularization parameter for different methods. To independently select the regularization parameter, we propose a cross-validation procedure which achieves a reconstruction quality close to the optimum. Additionally, we compare the outcome of seven different image reconstruction methods for cerebral functional DOT. The methods selected include reconstruction procedures that are already widely used for cerebral DOT [minimum l2-norm estimate (l2MNE) and truncated singular value decomposition], recently proposed sparse reconstruction algorithms [minimum l1- and a smooth minimum l0-norm estimate (l1MNE, l0MNE, respectively)] and a depth- and noise-weighted minimum norm (wMNE). Furthermore, we expand the range of algorithms for DOT by adapting two EEG-source localization algorithms [sparse basis field expansions and linearly constrained minimum variance (LCMV) beamforming]. Independent of the applied noise level, we find that the LCMV beamformer is best for single spot activations with perfect location and focality of the results, whereas the minimum l1-norm estimate succeeds with multiple targets.


Differential regulation of lipoprotein kinetics by atorvastatin and fenofibrate in subjects with the metabolic syndrome.
The metabolic syndrome is characterized by insulin resistance and abnormal apolipoprotein AI (apoAI) and apolipoprotein B-100 (apoB) metabolism that may collectively accelerate atherosclerosis. The effects of atorvastatin (40 mg/day) and micronised fenofibrate (200 mg/day) on the kinetics of apoAI and apoB were investigated in a controlled cross-over trial of 11 dyslipidemic men with the metabolic syndrome. ApoAI and apoB kinetics were studied following intravenous d(3)-leucine administration using gas-chromatography mass spectrometry with data analyzed by compartmental modeling. Compared with placebo, atorvastatin significantly decreased (P < 0.001) plasma concentrations of cholesterol, triglyceride, LDL cholesterol, VLDL apoB, intermediate-density lipoprotein (IDL) apoB, and LDL apoB. Fenofibrate significantly decreased (P < 0.001) plasma triglyceride and VLDL apoB and elevated HDL(2) cholesterol (P < 0.001), HDL(3) cholesterol (P < 0.01), apoAI (P = 0.01), and apoAII (P < 0.001) concentrations, but it did not significantly alter LDL cholesterol. Atorvastatin significantly increased (P < 0.002) the fractional catabolic rate (FCR) of VLDL apoB, IDL apoB, and LDL apoB but did not affect the production of apoB in any lipoprotein fraction or in the turnover of apoAI. Fenofibrate significantly increased (P < 0.01) the FCR of VLDL, IDL, and LDL apoB but did not affect the production of VLDL apoB. Relative to placebo and atorvastatin, fenofibrate significantly increased the production (P < 0.001) and FCR (P = 0.016) of apoAI. Both agents significantly lowered plasma triglycerides and apoCIII concentrations, but only atorvastatin significantly lowered (P < 0.001) plasma cholesteryl ester transfer protein activity. Neither treatment altered insulin resistance. In conclusion, these differential effects of atorvastatin and fenofibrate on apoAI and apoB kinetics support the use of combination therapy for optimally regulating dyslipoproteinemia in the metabolic syndrome.


Antithyroid drugs and Graves' disease--prospective randomized assessment of long-term treatment.
Although antithyroid drugs (ATD) are widely used in the treatment of Graves' disease, management protocols, especially treatment duration, remain a subject of debate. The rate of relapse after short-term regimens of less than 6 months with ATD at decreasing doses is higher than after longer treatments from 12 to 24 months. As no prospective study has provided data on even longer protocols exceeding 2 years, we conducted a prospective trial to determine potential benefits of a 42-month treatment compared with an 18-month treatment. The aim of this prospective randomized trial was to compare relapse rates achieved two years after treatment withdrawal in patients who received carbimazole at decreasing doses for 18 months (n = 62) vs 42 months (n = 72). In addition to clinical relapse rate, the percentage of patients who normalized antithyroperoxidase (TPO) antibody and anti-TSH receptor stimulating antibody (TSAb) levels and early iodine uptake at the end of treatment were assessed as outcome criteria. The relapse rate two years after discontinuation of treatment did not differ significantly in patients treated for 18 months from those treated for 42 months (36% vs 29%, NS). At the end of treatment, there was no significant difference between the two groups in the percentage of anti-TPO positive patients (53% vs 46%, NS) or early iodine uptake (27% vs 21%, NS). Although the percentage of patients with TSAb was significantly lower in the 42-month treatment group (18% vs 42%, P = 0.004) at treatment withdrawal, the percentage of TSAb-positive patients did not significantly decrease between 18 and 42 months in this group (27% vs 18%, NS). Treatment duration greater than 18 months did not improve remission rate determined 2 years after treatment withdrawal or immunological variables or early iodine uptake measured at the time of discontinuation of treatment. These findings would indicate that, when a defined duration treatment is planned, prolonging treatment beyond 18 months does not provide any additional benefit.


Synergistic inhibition of breast cancer cell lines with a dual inhibitor of EGFR-HER-2/neu and a Bcl-2 inhibitor.
The epidermal growth factor receptor (EGFR) (ErbB1) and HER-2/neu (ErbB2) are members of the ErbB family of receptor tyrosine kinases. These receptors are overexpressed in a variety of human tumors and overexpression generally correlates with poor prognosis and decreased survival. Lapatinib, a reversible inhibitor of both EGFR and HER-2/neu, has shown some success in achieving clinical responses in heavily pretreated advanced cancer patients. GW2974 is a reversible dual inhibitor similar to lapatinib, but GW2974 was not progressed to clinical trials due to pharmacokinetic issues. Bcl-2, an anti-apoptotic protein, is also overexpressed in a number of human tumors. Bcl-2 inhibitors induce apoptosis and sensitize cancer cells to other therapies. The purpose of this study was to assess the effects of combining ErbB and Bcl-2 inhibitors on the growth of human breast cancer cell lines. EGFR/HER-2/neu tyrosine kinase inhibitors (lapatinib and GW2974) were combined with Bcl-2 inhibitors (HA14-1 or GX15-070) and the anti-proliferative effects were determined by the MTT tetrazolium dye assay. Combinations were tested in MCF-7 human breast cancer cells, a HER-2/neu transfected MCF-7 cell line (MCF/18), and a tamoxifen-resistant MCF-7 cell line (MTR-3). A synergistic inhibitory effect was observed with the combination of inhibitors of EGFR-HER-2/neu (lapatinib or GW2974) and Bcl-2 (GX15-070 or HA14-1) on the growth of the MCF-7, MCF/18, and MTR-3 human breast cancer cell lines. This study suggests that simultaneously blocking the ErbB family of receptor tyrosine kinases and Bcl-2 family of proteins may be a benefit to breast cancer patients.


Women's Views About Domestic Violence: A Qualitative Study in Iran.
Violence against women is an urgent health priority in Iran. Designing effective programs for preventing and controlling the problem necessitates a thorough understanding of Iranian women and their perspectives regarding domestic violence. This study was aimed at exploring the domestic violence-related views of married women who were referred to health care facilities in Ahvaz, Iran. In this qualitative research, data were collected through four focus group discussions with 30 married women. All the discussions were recorded and transcribed, after which the data were classified separately. The main themes and subthemes were then manually derived from the data and analyzed. The five main themes identified were domestic violence against women in Ahvaz, behavioral influencing factors, nonbehavioral influencing factors, the necessity to empower women to prevent domestic violence, and recommendations for developing special training programs for Ahvazi women. Most of the participants were aware that domestic violence against women is a common occurrence in Iran. They were well aware of the definition of violence and expressed a belief that behavioral factors exert an important effect on the occurrence of the problem. They recommended the development of appropriate training programs that empower women to prevent the problem, the use of mass media to educate citizens about domestic violence, and the involvement of opinion leaders in eliminating the taboo against considering such violence a crime against Iranian women. Considering the views and ideas of women as consumers of educational services is a principle used to develop effective programs for preventing and controlling domestic violence. As indicated by the findings, the participants believe that empowering women must be treated as a priority in the Iranian health care system. However, they recommended differing approaches and methods of empowerment on the basis of their individual views and concerns.


Rapid recovery after oxford unicompartmental arthroplasty through a short incision.
Forty Oxford medial unicompartmental arthroplasties (UCAs) were performed through a short incision medial to the patellar tendon, without dislocation of the patella, using updated instruments (Oxford Knee Phase III, Biomet Ltd., Bridgend, UK). The rate of recovery of these knees (measured by the time taken to achieve straight-leg raising, 70 degrees of flexion, and independent stair climbing) was compared with that of 20 Oxford UCAs performed through an open approach with dislocation of the patella. Both groups were compared with 40 AGC (Biomet) total knee arthroplasties performed for osteoarthritis during the same time period. The average rate of recovery after the short-incision UCA was twice as fast as after open UCA and 3 times as fast as after total knee arthroplasty. Accuracy of implantation, assessed from 11 variables seen on fluoroscopically centered postoperative radiographs, was the same after UCA by the short-incision approach as after the open approach, suggesting that the short-term advantage of increased speed of recovery was gained without affecting the long-term results. We now employ the short incision with the phase III instruments for all UCAs.


The attitudes of medical students to research.
The workforce of 'physician--scientists' is ageing and decreasing in numbers. The responsibility to combat this trend rests on future generations of healthcare professionals and it is therefore valuable to evaluate medical students' attitudes towards research. To establish the attitudes of University of Cape Town (UCT) medical students towards research and to investigate the factors influencing these attitudes. An anonymous, cross--sectional, self--administered questionnaire was administered to medical students from years 1 to 6 studying medicine at UCT in 2011. Questions were primarily closed--ended and consisted of Likert scales. Out of a population of 1 195 medical students, 733 were sampled (63%); 65% were female, 53% were preclinical students (years 1 -- 3) and 47% were in their clinical years (year 4 -- 6). Overall, 61% of students had a positive attitude towards research and 74% felt that participation in research was important to their medical school education; 22% had been involved in voluntarily extracurricular research, 4% had presented at a scientific meeting and 3% had published in peer--reviewed journals. A number of perceived barriers to student research were identified including a lack of adequate training, time and research opportunities. Students believed that research was important and had a positive attitude towards it. However, few had been involved in voluntary research and produced work worthy of presentation and/or publication. Addressing identified barriers and improving students' attitudes may begin to reverse the trend in declining numbers of physician--scientists.


Balance Across Boundaries: Service-Learning from an International Perspective.
Service-Learning provides students, faculty and community partners an opportunity to go beyond classroom and laboratory instruction to the application of theoretical principles, and the development of civic responsibility by forging meaningful relationships with community partners. Service-learning also enables faculty to broaden the cultural sensitivity and international exposure of students by engaging students in directed, purposeful projects aimed at supporting the goals of both the college and the international partners. We have a unique opportunity in Exercise Science to make lasting changes and improve global conditions relating to student learning and the physical inactivity crisis. The purpose of this article is to define service-learning, describe different types of service-learning projects, and discuss service-learning opportunities in international settings.


Control of adaptive locomotion: effect of visual obstruction and visual cues in the environment.
Visual information regarding obstacle position and size is used for planning and controlling adaptive gait. However, the manner in which visual cues in the environment are used in the control of gait is not fully known. This research examined the effect of obstacle position cues on the lead and trail limb trajectories during obstacle avoidance with and without visual information of the lower limbs and obstacle (termed visual exproprioception). Eight subjects stepped over obstacles under four visual conditions: full vision without obstacle position cues, full vision with position cues, goggles without position cues and goggles with position cues. Goggles obstructed visual exproprioception of the lower limbs and the obstacle. Position cues (2 m tall) were placed beside the obstacle to provide visual cues regarding obstacle position. Obstacle heights were 2, 10, 20 and 30 cm. When wearing goggles and without position cues, a majority of the dependent measures (horizontal distance, toe clearance and lead stride length) increased for the 10, 20 and 30 cm obstacles. Therefore lower limb-obstacle visual exproprioception was important for the control of both limbs, even though with normal vision the trail limb was not visible during obstacle clearance. When wearing goggles, the presence of position cues, which provided on-line visual exproprioception of the self relative to the obstacle position in the anterior-posterior direction, returned lead and trail foot placements to full vision values. Lead toe clearance was not affected by the position cues, trail clearance decreased but was greater than values observed during full vision. Therefore, visual exproprioception of obstacle location, provided by visual cues in the environment, was more relevant than visual exproprioception of the lower limbs for controlling lead and trail foot placement.


MediaDB: a database of microbial growth conditions in defined media.
Isolating pure microbial cultures and cultivating them in the laboratory on defined media is used to more fully characterize the metabolism and physiology of organisms. However, identifying an appropriate growth medium for a novel isolate remains a challenging task. Even organisms with sequenced and annotated genomes can be difficult to grow, despite our ability to build genome-scale metabolic networks that connect genomic data with metabolic function. The scientific literature is scattered with information about defined growth media used successfully for cultivating a wide variety of organisms, but to date there exists no centralized repository to inform efforts to cultivate less characterized organisms by bridging the gap between genomic data and compound composition for growth media. Here we present MediaDB, a manually curated database of defined media that have been used for cultivating organisms with sequenced genomes, with an emphasis on organisms with metabolic network models. The database is accessible online, can be queried by keyword searches or downloaded in its entirety, and can generate exportable individual media formulation files. The data assembled in MediaDB facilitate comparative studies of organism growth media, serve as a starting point for formulating novel growth media, and contribute to formulating media for in silico investigation of metabolic networks. MediaDB is freely available for public use at https://mediadb.systemsbiology.net.


Genome-wide algorithm for detecting CNV associations with diseases.
SNP genotyping arrays have been developed to characterize single-nucleotide polymorphisms (SNPs) and DNA copy number variations (CNVs). Nonparametric and model-based statistical algorithms have been developed to detect CNVs from SNP data using the marker intensities. However, these algorithms lack specificity to detect small CNVs owing to the high false positive rate when calling CNVs based on the intensity values. Therefore, the resulting association tests lack power even if the CNVs affecting disease risk are common. An alternative procedure called PennCNV uses information from both the marker intensities as well as the genotypes and therefore has increased sensitivity. By using the hidden Markov model (HMM) implemented in PennCNV to derive the probabilities of different copy number states which we subsequently used in a logistic regression model, we developed a new genome-wide algorithm to detect CNV associations with diseases. We compared this new method with association test applied to the most probable copy number state for each individual that is provided by PennCNV after it performs an initial HMM analysis followed by application of the Viterbi algorithm, which removes information about copy number probabilities. In one of our simulation studies, we showed that for large CNVs (number of SNPs ≥ 10), the association tests based on PennCNV calls gave more significant results, but the new algorithm retained high power. For small CNVs (number of SNPs <10), the logistic algorithm provided smaller average p-values (e.g., p = 7.54e - 17 when relative risk RR = 3.0) in all the scenarios and could capture signals that PennCNV did not (e.g., p = 0.020 when RR = 3.0). From a second set of simulations, we showed that the new algorithm is more powerful in detecting disease associations with small CNVs (number of SNPs ranging from 3 to 5) under different penetrance models (e.g., when RR = 3.0, for relatively weak signals, power = 0.8030 comparing to 0.2879 obtained from the association tests based on PennCNV calls). The new method was implemented in software GWCNV. It is freely available at http://gwcnv.sourceforge.net, distributed under a GPL license. We conclude that the new algorithm is more sensitive and can be more powerful in detecting CNV associations with diseases than the existing HMM algorithm, especially when the CNV association signal is weak and a limited number of SNPs are located in the CNV.


Tracing the critical loci of binary fluid mixtures using molecular simulation.
Monte Carlo simulations are used to trace the critical loci for a number of binary mixtures. In particular, we use grand canonical Monte Carlo (GCMC) simulations with histogram reweighting and mixed-field finite-size scaling to determine the mixture critical lines. Two different classes of criticality are investigated. A mixture of methane and ethane displays type I criticality, exhibiting continuous mixing between the two species across the entire composition range. A methane-water mixture shows type IIIb criticality, with a discontinuity in the critical locus. Quantitative agreement is found between simulation and experimental critical loci for the methane-ethane system using no adjustable parameters for interactions in the mixture. For the water-methane system, we investigate the effect of the combining rules for the intermolecular interaction between the two species on the mixture critical locus. We also investigate several potentials for methane: a nonpolar exponential-6, an octopolar fixed partial charge, and a polarizable fluctuating charge model. Qualitative agreement between simulations and experiments is found for all potentials, but none are able to quantitatively capture the abrupt increase in the critical temperature as methane is added to the system.


Hsp70 regulates immune response in experimental autoimmune encephalomyelitis.
Heat shock protein (Hsp)70 is one of the most important stress-inducible proteins. Intracellular Hsp70 not only mediates chaperone-cytoprotective functions but can also block multiple steps in the apoptosis pathway. In addition, Hsp70 is actively released into the extracellular milieu, thereby promoting innate and adaptive immune responses. Thus, Hsp70 may be a critical molecule in multiple sclerosis (MS) pathogenesis and a potential target in this disease due to its immunological and cytoprotective functions. To investigate the role of Hsp70 in MS pathogenesis, we examined its immune and cytoprotective roles using both in vitro and in vivo experimental procedures. We found that Hsp70.1-deficient mice were more resistant to developing experimental autoimmune encephalomyelitis (EAE) compared with their wild-type (WT) littermates, suggesting that Hsp70.1 plays a critical role in promoting an effective myelin oligodendrocyte glycoprotein (MOG)-specific T cell response. Conversely, Hsp70.1-deficient mice that developed EAE showed an increased level of autoreactive T cells to achieve the same production of cytokines compared with the WT mice. Although a neuroprotective role of HSP70 has been suggested, Hsp70.1-deficient mice that developed EAE did not exhibit increased demyelination compared with the control mice. Accordingly, Hsp70 deficiency did not influence the vulnerability to apoptosis of oligodendrocyte precursor cells (OPCs) in culture. Thus, the immunological role of Hsp70 may be relevant in EAE, and specific therapies down-regulating Hsp70 expression may be a promising approach to reduce the early autoimmune response in MS patients.


The incorporation of NMDA receptors with a distinct subunit composition at nascent hippocampal synapses in vitro.
Activity-dependent synaptic rearrangements during CNS development require NMDA receptor activation. The control of NMDA receptor function by developmentally regulated subunit expression has been proposed as one mechanism for this receptor dependence. We examined the phenotype of synaptic and extrasynaptic NMDA receptors during the development of synaptic load using the NMDA receptor 2B (NR2B)-selective antagonist ifenprodil. In cultured rat hippocampal neurons when relatively few synapses had formed, the ifenprodil block of EPSCs was less than whole-cell currents, the latter of which included both synaptic and extrasynaptic receptors. At the same developmental stage, we found that extrasynaptic receptors outnumbered synaptic receptors by 3:1; thus whole-cell currents were dominated by the extrasynaptic population. We used the macroscopic kinetics of ifenprodil block to distinguish between the receptor populations. The ifenprodil kinetics of whole-cell currents from neurons before and during the development of synaptic load was comparable with that of whole-cell currents in HEK293 cells transfected with NR1 and NR2B cDNA, indicating that extrasynaptic receptors are largely NR1/NR2B heteromers. In contrast, synaptic receptors included both a highly ifenprodil-sensitive (NR1/NR2B) component as well as a second population with lower ifenprodil sensitivity; the reduced ifenprodil block of EPSCs was attributable to synaptic receptors with lower ifenprodil sensitivity rather than to the appearance of ifenprodil-insensitive (NR1/NR2A) receptors. Our data indicate that the synaptic NMDA receptor complement changes quickly after synapse formation. We suggest that synapses containing predominately NR1/NR2B heteromers represent "immature" sites, whereas mature sites express NMDA receptors with a distinct, presumably triheteromeric, subunit composition.


The Africa Ethics Working Group (AEWG): a model of collaboration for psychiatric genomic research in Africa.
The Africa Ethics Working Group (AEWG) is a South-South-North collaboration of bioethics and mental health researchers from sub-Saharan Africa, working to tackle emerging ethical challenges in global mental health research. Initially formed to provide ethical guidance for a neuro-psychiatric genomics research project, AEWG has evolved to address cross cutting ethical issues in mental health research aimed at addressing equity in North-South collaborations. Global South refers to economically developing countries (sub-Saharan Africa in this context) and Global North to economically developed countries (primarily Europe, UK and North America). In this letter we discuss lessons that as a group we have learnt over the last three years; lessons that similar collaborations could draw on. With increasing expertise from Global South as an outcome of several capacity strengthening initiatives, it is expected that the nature of scientific collaborations will shift to a truly equitable partnership. The AEWG provides a model to rethink contributions that each partner could make in these collaborations.


The M3S-based electric wheelchair for the people with disabilities in Taiwan.
This study aims to establish an electronic wheelchair system in Taiwan that conforms to multiple master-multiple slave (M3S) standards. The proposed system could enhance the safety and convenience of people with disabilities. The M3S-based head-controlled electric wheelchair consists of three parts: (A) the input device, (B) the output device, and (C) the safety device. Head movement can be used as the input control to cause the tilting device to produce a corresponding level of analog voltage (backward & forward/left & right) which is then transmitted to the analogy/digital conversion module to control the output device (wheelchair's motor). Ten subjects with C5 incompleted spinal cord injury were recruited in the clinical assessment. They were randomly assigned into groups A and B. In the group A, the subjects were assigned to operate the head-controlled wheelchair system with M3S standard before operating the head-controlled wheelchair system without M3S standard. In the group B, the subjects were assigned to operate the head-controlled wheelchair system without M3S standard before operating the head-controlled wheelchair system with M3S standard. Two subjects in the group B drop off due to their personal reasons. The time cost for group A in completing tasks 1, 2, and 3 with the M3S and without the M3S were insignificant (p>0.05). The time cost for completing in group B was insignificant (p>0.05). Thus, the wheelchair operating time is depended on the proficiency of the subjects, not the M3S standard added. The time cost for subjects to operate the wheelchair was determined by their proficiency, not the M3S standard control added to the system. However, the M3S-based system did realize the safety mechanism and complex auxiliary tools with and without the plug-in and play function.


Moving East: how the transnational tobacco industry gained entry to the emerging markets of the former Soviet Union-part II: an overview of priorities and tactics used to establish a manufacturing presence.
To explore how British American Tobacco (BAT), having established cigarette imports, responded to the opportunities for investment in cigarette manufacturing in the former Soviet Union (FSU). Analysis of documents held at the BAT archive in Guildford, UK. Considerable priority was attached to investing in the FSU. This led BAT to undertake a major organisational change and to intense competition to acquire assets. BAT used flawed economic arguments to persuade cash starved governments that its investment would reap economic rewards. It offered excise advice that disadvantaged governments while benefiting BAT, confused issues over pricing, and avoided competitive tendering. BAT targeted agriculture ministries, using its expertise in leaf production to differentiate itself from other potential investors. It subverted the principles of corporate social responsibility to promote itself as a business partner. BAT's task was made easier by the naivety of post-Soviet governments and by the international financial organisations' support for rapid economic reform. The latter permitted tobacco transnationals to penetrate markets before effective competitive tendering processes had been established, giving them the opportunity to minimise prices and establish monopolies. Many of the arguments employed when penetrating post-Soviet markets were highly misleading but governments lacked expertise to realise this. There is a need to build tobacco control capacity in transition economies, within and outside government, to ensure that governments are better informed of the true economic and health impacts of tobacco. Rapid transition from socialist to market economies without establishing regulatory institutional structures may be dangerous when investing companies use business practices that fall short of international standards.


Molecular mechanisms behind the antimicrobial activity of hop iso-α-acids in Lactobacillus brevis.
The main bittering component in beer, hop iso-α-acids, have been characterised as weak acids, which act as ionophores impairing microbial cells' function under acidic conditions as present in beer. Besides medium pH, divalent cations play a central role regarding the efficacy of the antimicrobial effect. The iso-α-acids' non-bitter derivatives humulinic acids can be found in isomerised hop extracts and can be generated during hop storage. Therefore, they have been under investigation concerning their influence on beer sensory properties. This study sketches the molecular mechanism behind iso-α-acids' antimicrobial activity in Lactobacillus (L.) brevis regarding their ionophore activity versus the dependence of the inhibitory potential on manganese binding, and suggests humulinic acids as novel tasteless food preservatives. We designed and synthesised chemically modified iso-α-acids to enhance the basic understanding of the molecular mechanism of antimicrobial iso-α-acids. It could be observed that a manganese-binding dependent transmembrane redox reaction (oxidative stress) plays a crucial role in inhibition. Privation of an acidic hydroxyl group neither erased ionophore activity, nor did it entirely abolish antimicrobial activity. Humulinic acids proved to be highly inhibitory, even outperforming iso-α-acids.


Feasibility of using a novel instrumented human head surrogate to measure helmet, head and brain kinematics and intracranial pressure during multidirectional impact tests.
Aim of the work is to present the feasibility of using an Instrumented Human Head Surrogate (IHHS-1) during multidirectional impacts while wearing a modern ski helmet. The IHHS-1 is intended to provide reliable and repeatable data for the experimental validation of FE models and for the experimental evaluation of modern helmets designed to enhance the degree of protection against multidirectional impacts. The new IHHS-1 includes 9 triaxial MEMS accelerometers embedded in a silicone rubber brain, independently molded and presenting lobes separation and cerebellum, placed into an ABS skull filled with surrogate cerebrospinal fluid. A triaxial MEMS gyroscope is placed at the brain center of mass. Intracranial pressure can be detected by eight pressure sensors applied to the skull internal surface along a transversal plane located at the brain center of mass and two at the apex. Additional MEMS sensors positioned over the skull and the helmet allow comparison between outer and inner structure kinematics and surrogate CSF pressure behavior. The IHHS-1 was mounted through a Hybrid III neck on a force platform and impacted with a striker connected to a pendulum tower, with the impact energies reaching 24J. Impact locations were aligned with the brain center of mass and located in the back (sagittal axis), right (90° from sagittal axis), back/right (45°), and front right (135°) locations. Following dynamic data were collected: values of the linear accelerations and angular velocities of the brain, skull and helmet; intracranial pressures inside the skull. Despite the relatively low intensity of impacts (HIC at skull max value 46), the skull rotational actions reached BrIC values of 0.33 and angular accelerations of 5216rad/s2, whereas brain angular acceleration resulted between 1,44 and 2,1 times lower with similar values of BrIC. The IHHS-1 is a physical head surrogate that can produce repeatable data for the interpretation of inner structures behavior during multidirectional impacts with or without helmets of different characteristics.


Brace treatment for patients with Scheuermann's disease - a review of the literature and first experiences with a new brace design.
In contemporary literature few have written in detail on the in-brace correction effects of braces used for the treatment of hyperkyphosis. Bradford et al. found their attempts effective, treating Scheuermann's kyphosis with Milwaukee braces, but their report did not specifically focus on in-brace corrections. White and Panjabi's research attempted to correct a curvature of > 50 degrees with the help of distraction forces, but consequently led to a reduction in patient comfort in the application of the Milwaukee brace. In Germany they avoid this by utitlising braces to treat hyperkyphosis that use transverse correction forces instead of distraction forces. Further efforts to reduce brace material have resulted in a special bracing design called kyphologic brace. The aim of this review is to present appropriate research to collect and evaluate possible in-brace corrections which have been achieved with brace treatment for hyperkyphosis. This paper introduces new methods of bracing and compares the results of these with other successful bracing concepts. 56 adolescents with the diagnosis of thoracic Scheuermann's hyperkyphosis or a thoracic idiopathic hyperkyphosis (22 girls and 34 boys) with an average age of 14 years (12-17 yrs.) were treated with the kyphologic brace between May 2007 and December 2008. The average Stagnara angle was 55,6 degrees (43-80). In-brace correction was recorded and compared to the initial angle using the t-test. The average Stagnara angle in the brace was 39 degrees . The average in-brace correction was 16.5 degrees (1-40 degrees ). The verage percentage of in-brace correction compared to the initial value was 36%. The differences were significant in the t-test (t = 5.31, p < 0,001). To make these results comparable to other studies, the kyphosis angle of 25 degrees was set to 0 for our sample in order to achieve a norm value adapted (NVA) percentage of in-brace correction. By doing this a correction of 54.1% was achieved. There was no correlation between the percentage of in-brace correction and the age of the patient, but a highly significant correlation between percentage of in-brace correction and the initial Stagnara angle. If we assume that outcome of brace treatment positively correlates with in-brace correction, the treatment should be initiated before the curvature angle exceeds 50 - 55 degrees in a growing adolescent. In scoliosis bracing, if the average in-brace correction equals > 15 degrees , then it is predicted that the result will lead to a final correction. Applying this to hyperkyphosis patients, the average in-brace correction with this brace was also > 15 degrees . We therefore estimated to achieve a favourable outcome using this brace type (once compliance was attained) especially when comparing the correction effects achieved with this new approach to the correction effects reported upon using the Milwaukee brace. The latter brace has been shown to lead to beneficial outcomes in long-term studies with comparable in-brace corrections. Conservative treatment of Scheuermann's hyperkyphosis in international literature is generally regarded as an effective treatment approach. Physiotherapy and bracing are the first-line treatments for this condition.An average in-brace correction of > 15 degrees as was achieved using the kyphologic brace predicts a favourable outcome.The kyphologic brace leads to in-brace corrections comparable to those of the Milwaukee brace, which has previously been shown to provide beneficial outcome in the long-term.A prospective follow-up study seems desirable before final conclusions can be drawn.Future studies should focus more on thoracolumbar and lumbar curve patterns, because these patterns may predict chronic low back pain in adulthood with reduced quality of life of the patients and high costs with respect to medical care and occupational sickness leave.Surgery according to international literature is rarely necessary in this condition.


Flavonoids in food and their health benefits.
There has been increasing interest in the research of flavonoids from dietary sources, due to growing evidence of the versatile health benefits of flavonoids through epidemiological studies. As occurrence of flavonoids is directly associated with human daily dietary intake of antioxidants, it is important to evaluate flavonoid sources in food. Fruits and vegetables are the main dietary sources of flavonoids for humans, along with tea and wine. However, there is still difficulty in accurately measuring the daily intake of flavonoids because of the complexity of existence of flavonoids from various food sources, the diversity of dietary culture, and the occurrence of a large amount of flavonoids itself in nature. Nevertheless, research on the health aspects of flavonoids for humans is expanding rapidly. Many flavonoids are shown to have antioxidative activity, free-radical scavenging capacity, coronary heart disease prevention, and anticancer activity, while some flavonoids exhibit potential for anti-human immunodeficiency virus functions. As such research progresses. further achievements will undoubtedly lead to a new era of flavonoids in either foods or pharmaceutical supplements. Accordingly, an appropriate model for a precise assessment of intake of flavonoids needs to be developed. Most recent research has focused on the health aspects of flavonoids from food sources for humans. This paper reviews the current advances in flavonoids in food, with emphasis on health aspects on the basis of the published literature, which may provide some guidance for researchers in further investigations and for industries in developing practical health agents.


Abetimus sodium for renal flare in systemic lupus erythematosus: results of a randomized, controlled phase III trial.
To investigate whether treatment with abetimus delays renal flare in patients with lupus nephritis. Secondary objectives included evaluation of the effect of abetimus on C3 levels, anti-double-stranded DNA (anti-dsDNA) antibody levels, use of high-dose corticosteroids and/or cyclophosphamide, and major systemic lupus erythematosus (SLE) flare. We conducted a randomized, placebo-controlled study of treatment with abetimus at 100 mg/week for up to 22 months in SLE patients. Three hundred seventeen patients with a history of renal flare and anti-dsDNA levels >15 IU/ml were randomized to a treatment group (158 abetimus, 159 placebo); 298 (94%) were enrolled in the intent-to-treat (ITT) population (145 abetimus, 153 placebo), based on the presence of high-affinity antibodies for the oligonucleotide epitope of abetimus at baseline screening. Abetimus did not significantly prolong time to renal flare, time to initiation of high-dose corticosteroid and/or cyclophosphamide treatment, or time to major SLE flare. However, there were 25% fewer renal flares in the abetimus group compared with the placebo group (17 of 145 abetimus-treated patients [12%] versus 24 of 153 placebo-treated patients [16%]). Abetimus treatment decreased anti-dsDNA antibody levels (P < 0.0001), and reductions in anti-dsDNA levels were associated with increases in C3 levels (P < 0.0001). More patients in the abetimus group experienced > or =50% reductions in proteinuria at 1 year, compared with the placebo group (nominal P = 0.047). Trends toward reduced rates of renal flare and major SLE flare were noted in patients treated with abetimus who had impaired renal function at baseline. Treatment with abetimus for up to 22 months was well tolerated. Abetimus at 100 mg/week significantly reduced anti-dsDNA antibody levels but did not significantly prolong time to renal flare when compared with placebo. Multiple positive trends in renal end points were observed in the abetimus treatment group.


Trends in public opinion on alcohol policy measures: Ontario 1989-1998.
This article presents trend data concerning public opinion on alcohol policy in the Canadian province of Ontario over a 10-year period (1989-98), highlights the currently debated issue of private venues for retail alcohol sales and assesses correspondence between public opinion and actual and proposed policy decisions. Selected policy-related items from nine probability surveys on representative samples of male and female Ontario adults (range of unweighted n 's: 953 to 1,947) were analyzed by means of logistic regression. We found strong support for the status quo for a number of items, including beer and liquor store hours, corner store sales and taxes. Across all years, less than 6% of the total sample wanted to lower the legal drinking age. Over time, a linear trend showed a gradual but not entirely consistent development of attitudes among the Ontario public, favoring relaxation of some controls. However, contrary to this trend, disapproval of retail sales in corner stores increased significantly from 1992 to 1996. Demographic breakdown shows that relaxation of controls is most favored by those who report consumption of five or more drinks per occasion at least weekly over the past 12 months, and most strongly opposed by women and nondrinkers. Of those who seldom or never consume five or more drinks per occasion, the majority express satisfaction with the status quo. These data call into question the suitability of changes in alcohol policy that would diminish controls. It is of particular interest that there seems to be little public support for privatization proposals in the province. Public opinion against comer store sales of alcoholic beverages increased over time.


Sugar-sweetened beverages and risk of obesity and type 2 diabetes: epidemiologic evidence.
In recent decades, temporal patterns in SSB intake have shown a close parallel between the upsurge in obesity and rising levels of SSB consumption. SSBs are beverages that contain added caloric sweeteners such as sucrose, high-fructose corn syrup or fruit-juice concentrates, all of which result in similar metabolic effects. They include the full spectrum of soft drinks, carbonated soft drinks, fruitades, fruit drinks, sports drinks, energy and vitamin water drinks, sweetened iced tea, cordial, squashes, and lemonade, which collectively are the largest contributor to added sugar intake in the US. It has long been suspected that SSBs have an etiologic role in the obesity epidemic, however only recently have large epidemiological studies been able to quantify the relationship between SSB consumption and long-term weight gain, type 2 diabetes (T2DM) and cardiovascular disease (CVD) risk. Experimental studies have provided important insight into potential underlying biological mechanisms. It is thought that SSBs contribute to weight gain in part by incomplete compensation for energy at subsequent meals following intake of liquid calories. They may also increase risk of T2DM and CVD as a contributor to a high dietary glycemic load leading to inflammation, insulin resistance and impaired beta-cell function. Additional metabolic effects from the fructose fraction of these beverages may also promote accumulation of visceral adiposity, and increased hepatic de novo lipogenesis, and hypertension due to hyperuricemia. Consumption of SSBs should therefore be replaced by healthy alternatives such as water, to reduce risk of obesity and chronic diseases.


Alteration of the bone tissue material properties in type 1 diabetes mellitus: A Fourier transform infrared microspectroscopy study.
Type 1 diabetes mellitus (T1DM) is a severe disorder characterized by hyperglycemia and hypoinsulinemia. A higher occurrence of bone fractures has been reported in T1DM, and although bone mineral density is reduced in this disorder, it is also thought that bone quality may be altered in this chronic pathology. Vibrational microscopies such as Fourier transform infrared microspectroscopy (FTIRM) represent an interesting approach to study bone quality as they allow investigation of the collagen and mineral compartment of the extracellular matrix in a specific bone location. However, as spectral feature arising from the mineral may overlap with those of the organic component, the demineralization of bone sections should be performed for a full investigation of the organic matrix. The aims of the present study were to (i) develop a new approach, based on the demineralization of thin bone tissue section to allow a better characterization of the bone organic component by FTIRM, (ii) to validate collagen glycation and collagen integrity in bone tissue and (iii) to better understand what alterations of tissue material properties in newly forming bone occur in T1DM. The streptozotocin-injected mouse (150 mg/kg body weight, injected at 8 weeks old) was used as T1DM model. Animals were randomly allocated to control (n = 8) or diabetic (n = 10) groups and were sacrificed 4 weeks post-STZ injection. Bones were collected at necropsy, embedded in polymethylmethacrylate and sectioned prior to examination by FTIRM. FTIRM collagen parameters were collagen maturity (area ratio between 1660 and 1690 cm(-1) subbands), collagen glycation (area ratio between the 1032 cm(-1) subband and amide I) and collagen integrity (area ratio between the 1338 cm(-1) subband and amide II). No significant differences in the mineral compartment of the bone matrix could be observed between controls and STZ-injected animals. On the other hand, as compared with controls, STZ-injected animals presented with significant higher value for collagen maturity (17%, p = 0.0048) and collagen glycation (99%, p = 0.0121), while collagen integrity was significantly lower by 170% (p = 0.0121). This study demonstrated the profound effect of early T1DM on the organic compartment of the bone matrix in newly forming bone. Further studies in humans are required to ascertain whether T1DM also lead to similar effect on the quality of the bone matrix.


Sexual intercourse and cerebral aneurysmal rupture: potential mechanisms and precipitants.
Aneurysmal subarachnoid hemorrhage (SAH) is a significant cause of death in young and middle-aged individuals and causes tremendous morbidity in affected patients. Despite the identification of various risk factors, the series of events leading to the formation, growth, and rupture of intracranial aneurysms is poorly understood. Cerebral aneurysm rupture has been associated with sexual intercourse and other forms of physical exercise. In fact, multiple case series reported that coitus was the immediate preceding activity in 3.8-14.5% of patients suffering from aneurysmal SAH. This may be related to the large elevations in mean arterial blood pressure that occur in both males and females during sexual intercourse (130-175 and 125-160 mm Hg, respectively). While coitus and physical exercise share important physiological similarities, each may differentially affect the probability that a preformed aneurysm will rupture. In this literature review and synthesis, the authors analyze the physiological human response to sexual intercourse in an effort to delineate those factors that may precipitate aneurysmal rupture. The authors' analysis is based on the original data collected by Masters and Johnson. To the authors' knowledge, this is the first review to address the link between sexual intercourse and intracranial aneurysmal rupture. While actual measurements of the physiological variables relevant to SAH were not performed in this article, the authors make reasonable assumptions based on the available data to help elucidate the mechanism of sexually induced aneurysmal rupture.


Diode-pumped continuous wave and Q-switched operation of Nd:CaYAlO₄ crystal.
The continuous wave (CW) and passively Q-switched performances of Nd:CaYAlO(4) crystal with both a- and c-cut were demonstrated. The CW output powers of 1.15 W and 1.26 W were obtained under the pump power of 8.96 W with slope efficiencies of 15.2% and 16.8% for a- and c-cut samples, respectively. As a result, new dual-wavelength all-solid-state lasers at 1080 nm and 1081 nm were achieved with c-cut crystal. By using Cr(4+):YAG wafer as saturable absorber, we performed Q-switching experiments. The highest average output powers and shortest pulse widths were measured to be 0.798 W, 10.6 ns and 0.537 W, 9.6 ns for a- and c-cut samples, respectively.


Dialectical behavior therapy and domains of functioning over two years.
Individuals diagnosed with borderline personality disorder (BPD) tend to have a significant degree of functional impairment across a range of social and occupational spheres including difficulty finding and maintaining satisfying employment, housing, or relationships. Understanding what factors are associated with functional impairment will enable treatment providers to move those diagnosed with BPD beyond symptomatic recovery and toward a life worth living. This paper investigated the trajectories and predictors of functional outcomes for suicidal women with BPD (N = 99) during a treatment outcome study of Dialectical Behavior Therapy (DBT). Results revealed that participants had statistical and clinical improvements in functioning. Individuals with high emotion dysregulation displayed poorer psychosocial functioning at the subsequent assessment period and slower rates of change, which was also seen in reverse for one psychosocial functioning variable. Skills use was not related to individual trajectories in functioning. This study highlights the relationship of emotion dysregulation to functioning within a sample of suicidal women with BPD as well as the importance researching multiple domains in functioning.


Treatment satisfaction is associated with improved quality of life in patients treated with inhaled treprostinil for pulmonary arterial hypertension.
Patient treatment satisfaction is likely to be a highly relevant outcome measure in pulmonary arterial hypertension (PAH), a condition for which the benefits of treatment must be weighed against frequent, undesirable side effects, inconvenience, and complications associated with therapy. In this study, we sought to evaluate the psychometric properties of a patient-reported treatment satisfaction measure and its relationship to quality of life (QoL) among patients transitioning from inhaled iloprost (iILO) to inhaled treprostinil (iTRE). We studied treatment satisfaction among 66 subjects with PAH in a single-arm, open-label, multi-center trial of iTRE following transition from iILO. Treatment satisfaction was assessed using the Treatment Satisfaction Questionnaire for Medication (TSQM, version 1.4) administered to subjects immediately before and 12 weeks after transition of inhaled therapy. The TSQM is comprised of 4 domains: effectiveness, side effects, convenience, and global satisfaction. Scores range from 0 to 100 with higher scores indicating greater satisfaction. Six-minute walk distance (6MWD), functional class, adverse events, drug administration time, and PAH-specific QoL (CAMPHOR) were concurrently assessed. Domains of the TSQM demonstrated evidence of strong internal consistency at baseline and at 12 weeks (Cronbach α = 0.88-0.93). Transition from iILO to iTRE was associated with an improvement in 3 of 4 TSQM domains: effectiveness (+20 ± 21, p < 0.0001), side effects (0 ± 22, p = 0.97), convenience (+39 ± 26, p < 0.0001), and global satisfaction (+20 ± 24, p = 0.0005). Change in effectiveness scores correlated with change in 6MWD (r = 0.43, p = 0.0004) and side effects scores at 12 weeks correlated inversely with number of severity-weighted treatment-emergent adverse events (r = -0.44, p = 0.0002). In multiple regression models adjusted for baseline characteristics, changes in effectiveness and convenience satisfaction scores were significantly associated with improvement in PAH-specific QoL (p = 0.002 and p = 0.01). The TSQM demonstrated acceptable performance characteristics in patients with PAH. Changes in treatment satisfaction resulting from transitioning from iILO to iTRE were associated with improvements in PAH-specific QoL.


Transcranial magnetic stimulation as a therapeutic tool in psychiatry: what do we know about the neurobiological mechanisms?
Potential therapeutic properties of repetitive transcranial magnetic stimulation (rTMS) have been suggested in several psychiatric disorders such as depression, mania, obsessive-compulsive disorder, posttraumatic stress disorder and schizophrenia. By inducing electric currents in brain tissue via a time-varying strong magnetic field, rTMS has the potential to either directly or trans-synaptically modulate neuronal circuits thought to be dysfunctional in these psychiatric disorders. However, in order to optimize rTMS for therapeutic use, it is necessary to understand the neurobiological mechanisms involved, particularly the nature of the changes induced and the brain regions affected. Compared to the growing number of clinical studies on its putative therapeutic properties, the studies on the basic mechanisms of rTMS are surprisingly scarce. rTMS currently still awaits clinical routine administration although,there is compelling evidence that it causes changes in neuronal circuits as reflected by behavioural changes and decreases in the activity of the hypothalamic-pituitary-adrenocortical system. Both alterations suggest regional changes in neurotransmitter/neuromodulator release, transsynaptic efficiency, signaling pathways and in gene transcription. Together, these changes are, in part, reminiscent of those accompanying antidepressant drugs.


Combat and herbicide exposures in Vietnam among a sample of American Legionnaires.
A cross-sectional survey of 6810 randomly selected members of The American Legion in six states who served in the U.S. Armed Forces during the Vietnam Era was conducted by a mailed questionnaire. Combat stress was evaluated by a previously validated eight-item scale. Exposure to Agent Orange and other herbicides was estimated via exposure probability index previously developed by the authors which uses an algorithm based on the combined Air Force and Joint Services HERBS files of spray data. Two-fifths of the men had served in Southeast Asia, generally at the same time during which the major proportion of herbicides were used; the remaining subjects served elsewhere. Both combat and Agent Orange exposure exhibited distinct, meaningful distributions among Vietnam veterans with service in Southeast Asia and were also correlated with each other (r = 0.24). Our analysis demonstrates conclusively that mere presence in Vietnam cannot be used as a proxy for exposure to Agent Orange. Categorization of Vietnam veterans according to herbicide exposure can be successfully accomplished, based on an existing detailed herbicide application data base. This analysis, together with the consistent dose-related results obtained in this series of papers on health and behavioral effects, demonstrates the utility of questionnaire-derived herbicide and combat exposure measures for epidemiologic study of Vietnam veterans.


Extracellular ATP as a trigger for apoptosis or programmed cell death.
Extracellular ATP is shown here to induce programmed cell death (or apoptosis) in thymocytes and certain tumor cell lines. EM studies indicate that the ATP-induced death of thymocytes and susceptible tumor cells follows morphological changes usually associated with glucocorticoid-induced apoptosis of thymocytes. These changes include condensation of chromatin, blebbing of the cell surface, and breakdown of the nucleus. Cytotoxicity assays using double-labeled cells show that ATP-mediated cell lysis is accompanied by fragmentation of the target cell DNA. DNA fragmentation can be set off by ATP but not the nonhydrolysable analogue ATP gamma S nor other nucleoside-5'-triphosphates. ATP-induced DNA fragmentation but not ATP-induced 51Cr release can be blocked in cells pretreated with inhibitors of protein or RNA synthesis or the endonuclease inhibitor, zinc; whereas pretreatment with calmidazolium, a potent calmodulin antagonist, blocks both DNA fragmentation and 51Cr release. The biochemical and morphological changes caused by ATP are preceded by a rapid increase in the cytoplasmic calcium of the susceptible cell. Calcium fluxes by themselves, however, are not sufficient to cause apoptosis, as the pore-forming protein, perforin, causes cell lysis without DNA fragmentation or the morphological changes associated with apoptosis. Taken together, these results indicate that ATP can cause cell death through two independent mechanisms, one of which, requiring an active participation on the part of the cell, takes place through apoptosis.


The origins of human prosociality: Cultural group selection in the workplace and the laboratory.
Human prosociality toward nonkin is ubiquitous and almost unique in the animal kingdom. It remains poorly understood, although a proliferation of theories has arisen to explain it. We present evidence from survey data and laboratory treatment of experimental subjects that is consistent with a set of theories based on group-level selection of cultural norms favoring prosociality. In particular, increases in competition increase trust levels of individuals who (i) work in firms facing more competition, (ii) live in states where competition increases, (iii) move to more competitive industries, and (iv) are placed into groups facing higher competition in a laboratory experiment. The findings provide support for cultural group selection as a contributor to human prosociality.


Blood-derived dermal langerin+ dendritic cells survey the skin in the steady state.
Langerin is a C-type lectin receptor that recognizes glycosylated patterns on pathogens. Langerin is used to identify human and mouse epidermal Langerhans cells (LCs), as well as migratory LCs in the dermis and the skin draining lymph nodes (DLNs). Using a mouse model that allows conditional ablation of langerin(+) cells in vivo, together with congenic bone marrow chimeras and parabiotic mice as tools to differentiate LC- and blood-derived dendritic cells (DCs), we have revisited the origin of langerin(+) DCs in the skin DLNs. Our results show that in contrast to the current view, langerin(+)CD8(-) DCs in the skin DLNs do not derive exclusively from migratory LCs, but also include blood-borne langerin(+) DCs that transit through the dermis before reaching the DLN. The recruitment of circulating langerin(+) DCs to the skin is dependent on endothelial selectins and CCR2, whereas their recruitment to the skin DLNs requires CCR7 and is independent of CD62L. We also show that circulating langerin(+) DCs patrol the dermis in the steady state and migrate to the skin DLNs charged with skin antigens. We propose that this is an important and previously unappreciated element of immunosurveillance that needs to be taken into account in the design of novel vaccine strategies.


Pharmacokinetic of diclofenac in the presence and absence of glibenclamide in the rat.
There is evidence that the sulfonylurea antidiabetic agent glibenclamide reduces the analgesic action of non-steroidal anti-inflammatory drugs (NSAIDs), opioids and neuromodulators in animal models. Therefore, in view of the vast clinical uses and interactions of NSAIDs with commonly used therapeutic agents, the interaction of the NSAID diclofenac and glibenclamide was investigated about pharmacokinetic profile and antinociceptive effect in rats. Antinociception was assessed using the formalin test. Fifty microliters of diluted formalin was injected s.c. into the dorsal surface of the right hind paw. Nociceptive behavior was quantified as the number of flinches of the injected paw during 60 min after injection. Rats were treated with oral administration of vehicle or increasing doses of diclofenac (3-18 mg/kg) before formalin injection. To determine the pharmacodynamic interaction between diclofenac and glibenclamide, the effect of oral administration of glibenclamide (1-30 mg/kg) on the antinociceptive effect induced by diclofenac (18 mg/kg, p.o.) was assessed. To evaluate the pharmacokinetic interaction between diclofenac and glibenclamide, the effect of glibenclamide (10 mg/kg, p.o.) on the pharmacokinetic of diclofenac (18 mg/kg, p.o.) was studied in the rat. Blood samples were taken over 8 h and analyzed using a validated high-performance liquid chromatography method to generate the pharmacokinetic profile of diclofenac. Pharmacokinetic parameters were estimated using noncompartmental analysis. Systemic administration of diclofenac produced a dose-dependent antinociceptive effect in the formalin test. Systemic treatment with glibenclamide prevented diclofenac-induced antinociception. In pharmacokinetic interaction study, no significant (P>0.05) change in diclofenac concentration-time profiles in the presence of glibenclamide was detected. The experimental findings suggest that systemic glibenclamide is able to block the diclofenac-induced antinociception in the rat formalin test. Besides, this antagonism was not produced by diminution in the bioavailability of diclofenac. Likewise, the validated assay had sufficient accuracy and precision for pharmacokinetic determination of diclofenac in the rat.


Homotypic versus heterotypic continuity of anxiety symptoms in young adolescents: evidence for distinctions between DSM-IV subtypes.
to investigate homotypic and heterotypic longitudinal patterns of symptoms of separation anxiety disorder (SAD), generalized anxiety disorder (GAD), social phobia (SoPh), panic disorder (PD), and obsessive compulsive disorder (OCD) in young adolescents from the Dutch general population. 2,067 individuals (51.4% girls) from a Dutch community sample, who were assessed for the first time when they were aged 10 to 12 years, were followed up across a period of two years. At both assessments, anxiety symptoms were assessed with the RCADS, a self-report questionnaire. Regression analyses indicated that homotypic continuity was relatively high for SAD, GAD, and SoPh symptoms, and for PD in girls. In many studies, anxiety disorders are treated as one group of disorders, and some widely used assessment instruments, such as the Child Behavior Checklist, do not even contain scales that tap different anxiety dimensions. In the present study, evidence for homotypic continuity was found, especially for symptoms of separation, social, and generalized anxiety, and for symptoms of panic disorder in girls, underscoring the usefulness of making distinctions between different anxiety constructs.


Tripterygium wilfordii Hook F as Maintenance Treatment for Crohn's Disease.
The traditional Chinese medicine, Tripterygium wilfordii Hook F (TwHF) is widely used to treat Crohn's disease (CD) in China. The authors compared different doses of TwHF with mesalazine in 198 patients with CD over a 52-week period. Subjects were randomized to receive mesalazine (3 g/d), low-dose TwHF (1.5 mg·kg·d), or high-dose TwHF (2.0 mg·kg·d). A total of 137 patients completed the study. At week 52, a significant lower proportion of patients in the high-dose TwHF group (7/71) had clinical recurrence compared with patients in the low-dose TwHF (15/68, P = 0.047) or mesalazine group (17/59, P = 0.006), whereas the difference between the low-dose TwHF group and the mesalazine group was not significant (P = 0.503). Patients receiving mesalazine experienced less adverse events than those receiving high-dose TwHF (P = 0.029) and those receiving low-dose TwHF (P = 0.048), but no significant difference was found about drug adverse events resulted withdrawal in the 3 groups (P > 0.05). In addition, compared with low-dose TwHF and mesalazine, the authors also detected significant superiority of high-dose TwHF arm in the decrease of CDAI and SESCD (P < 0.05). A 2.0 mg/kg daily TwHF was well tolerated and prolonged remission in patients with CD.


Left ventricular stiffness estimated by diastolic wall strain is associated with paroxysmal atrial fibrillation in structurally normal hearts.
Left ventricular (LV) diastolic dysfunction depends on an impaired relaxation and stiffness. Abnormal LV relaxation contributes to the development of atrial fibrillation (AF), but the role of LV stiffness in AF remains unclear. Diastolic wall strain (DWS), a load-independent, noninvasive direct measure of LV stiffness, correlates with prevalent AF. This study included 328 consecutive subjects with structurally normal hearts: 164 paroxysmal AF patients and 164 age- and sex-matched (1:1) controls. We calculated the DWS from the M-mode echocardiographic measurements of the LV posterior wall thickness at end-systole and end-diastole during sinus rhythm. The DWS was lower in the AF patients (0.35 ± 0.07) than in the controls (0.41 ± 0.06; P < 0.001). After adjusting for the risk factors of AF using a conditional logistic regression analysis, a history of hypertension, plasma brain-type natriuretic peptide level, and DWS were independently associated with AF prevalence, whereas body mass index, LV mass index, left atrial volume, and any conventional indices of the diastolic function were not. A low DWS (<0.380) was the strongest indicator of AF (odds ratio: 6.22, 95% confidence interval: 3.08-14.2, P < 0.001). Increased LV stiffness estimated by DWS was a strong determinant of the prevalence of AF. LV stiffness may play a role in the pathogenesis of paroxysmal AF in structurally normal hearts.


Hospices' preparation and practices for quality measurement.
Hospice and palliative care organizations need to measure and analyze quality of care, in response to national palliative care practice guidelines and new hospice regulatory requirements. Little is known about hospices' readiness to meet this new mandate. We analyzed data from a national survey of hospices to describe preparation and practices for quality measurement and research and to examine associated organizational characteristics. Web-based survey of hospice staff responsible for quality of care. Survey respondents represented 652 National Hospice and Palliative Care Organization (NHPCO) member hospice organizations; 52% were participating in the NHPCO Quality Partners program. Most of these hospices involve clinical providers in decisions to change care practices (69%) and participate in quality improvement projects (64%), but research participation is uncommon (16%). Many hospices collect data about staff certification and training (76%) and use family surveys to measure care quality (70%). A minority of hospices have clinical data in electronic format (13%-29%). Large size, multiple sites, government ownership, and presence of a change leader in the organization were the characteristics associated with greater preparation for quality improvement and research. Current organizational activities, data collection rates, and use of electronic data systems may limit hospices' preparation and practices related to quality improvement and research participation; larger size and designation of a change leader are associated with greater capacity. Hospices may need technical assistance and training to provide for meaningful measurement of quality of care.


Sub-categorisation of skin corrosive chemicals by the EpiSkin™ reconstructed human epidermis skin corrosion test method according to UN GHS: revision of OECD Test Guideline 431.
The EpiSkin™ skin corrosion test method was formally validated and adopted within the context of OECD TG 431 for identifying corrosive and non-corrosive chemicals. The EU Classification, Labelling and Packaging Regulation (EU CLP) system requires the sub-categorisation of corrosive chemicals into the three UN GHS optional subcategories 1A, 1B and 1C. The present study was undertaken to investigate the usefulness of the validated EpiSkin™ test method to identify skin corrosive UN GHS Categories 1A, 1B and 1C using the original and validated prediction model and adapted controls for direct MTT reduction. In total, 85 chemicals selected by the OECD expert group on skin corrosion were tested in three independent runs. The results obtained were highly reproducible both within (>80%) and between (>78%) laboratories when compared with historical data. Moreover the results obtained showed that the EpiSkin™ test method is highly sensitive (99%) and specific (80%) in discriminating corrosive from non-corrosive chemicals and allows reliable and relevant identification of the different skin corrosive UN GHS subcategories, with high accuracies being obtained for both UN GHS Categories 1A (83%) and 1B/1C (76%) chemicals. The overall accuracy of the test method to subcategorise corrosive chemicals into three or two UN GHS subcategories ranged from 75% to 79%. Considering those results, the revised OECD Test Guideline 431 permit the use of EpiSkin™ for subcategorising corrosive chemicals into at least two classes (Category 1A and Category 1B/1C).


Interspecific Signaling Between the Parasitic Plant and the Host Plants Regulate Xylem Vessel Cell Differentiation in Haustoria of Cuscuta campestris.
The genus Cuscuta is stem parasitic angiosperms that parasitize a wide range of vascular plants via de novo formation of a distinctive parasitic organ called a haustorium. In the developing haustorium, meristematic cells, which are initiated from the stem cortical tissue, differentiate into haustorial parenchyma cells, which elongate, penetrate into the host tissues, and finally connect with the host vasculature. This interspecific vasculature connection allows the parasite to uptake water and nutrients from the host plant. Although histological aspects of haustorium development have been studied extensively, the molecular mechanisms underlying vasculature development and the interspecific connection with the host vasculature remain largely unknown. To gain insights into the interspecific cell-to-cell interactions involved in haustorium development, we established an in vitro haustorium induction system for Cuscuta campestris using Arabidopsis thaliana rosette leaves as the host plant tissue. The in vitro induction system was used to show that interaction with host tissue was required for the differentiation of parasite haustorial cells into xylem vessel cells. To further characterize the molecular events occurring during host-dependent xylem vessel cell differentiation in C. campestris, we performed a transcriptome analysis using samples from the in vitro induction system. The results showed that orthologs of genes involved in development and proliferation of vascular stem cells were up-regulated even in the absence of host tissue, whereas orthologs of genes required for xylem vessel cell differentiation were up-regulated only after some haustorial cells had elongated and contacted the host xylem. Consistent results were obtained by another transcriptome analysis of the haustorium development in C. campestris undergoing parasitization of an intact host plant. These findings suggest the involvement of host-derived signals in the regulation of non-autonomous xylem vessel differentiation and suggest that its connection to the host xylem during the haustorium development activates a set of key genes for differentiation into xylem vessel cells.